Field of the Invention
The present invention relates to the technical field of crystallization in pharmaceutical chemistry. Specifically, the present invention relates to canagliflozin Monohydrate and its crystalline forms, preparation methods, pharmaceutical compositions and uses thereof.
Background
Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor. It can lower blood glucose concentration by blocking reabsorption of glucose in the renal tubular into the bloodstream and increasing urinary glucose excretion. Canagliflozin was developed by Johnson & Johnson's Janssen Pharmaceuticals and approved for marketing by the FDA in March 2013 under the trade name of Invokana. The drug was approved for treatment of type II diabetes in adults, but unsuitable for type I diabetes or diabetic ketoacidosis. Its dosage form is capsule-shaped film-coated tablets. Two strengths are 100 mg and 300 mg, the 100 mg tablet is yellow, the 300 mg tablet is white. The active ingredient is canagliflozin hemihydrate.
The chemical name of Canagliflozin is (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol. Its molecular formula is C24H25FO5S and molecular weight is 444.52. The chemical structural formula of Canagliflozin is shown below:

Patent documents WO2005/012326A1 and U.S. Pat. No. 7,943,788B2 disclosed canagliflozin and preparation methods thereof. For convenience, the canagliflozin prepared according to U.S. Pat. No. 7,943,788B2 is referred to as the known canagliflozin in the present application.
Patent documents WO2008/069327A1 and U.S. Pat. No. 7,943,582B2 disclosed a crystalline form of canagliflozin hemihydrate and its preparation methods, and characterized it by XRPD and FTIR. For convenience, it is referred to as canagliflozin hemihydrate Form hH1 in the present application.
Patent document CN201310496416.2 disclosed another crystalline form of canagliflozin hemihydrate and its preparation methods, and characterized it by XRPD, IR, DSC and TGA. For convenience, it is referred to as canagliflozin hemihydrate Form hH2 in the present application.
Patent document WO2009/035969A1 disclosed a crystalline form of canagliflozin and its preparation methods, and characterized it by XRPD. For convenience, it is referred to as canagliflozin Form A in the present application.
Patent document CN201310556655.2 disclosed canagliflozin crystalline Form B and its preparation methods, and characterized it by XRPD and DSC. For convenience, it is referred to as canagliflozin Form B in the present application.
Patent document CN201310617597.X disclosed canagliflozin Form C and Form D and their preparation methods. Form C was characterized by XRPD, DSC and TGA, and Form D was characterized by XRPD.
Patent document WO2011/142478A1 disclosed tablets containing canagliflozinb hemihydrate Form hH1. WO2012/006298A2 disclosed bilayer tablets containing canagliflozin hemihydrate as well as their preparation methods.
The present inventors repeated the prior art processes for making the known canagliflozin and canagliflozin Form A, Form B, Form C and Form D, canagliflozin hemihydrate Form hH1 and canagliflozin hemihydrate Form hH2 disclosed in the above documents and tested their properties. The results indicated that the known canagliflozin and canagliflozin Form A were not stable in water, as they failed to maintain their original crystalline forms in the competitive stability test in water and both changed forms; Cangaliflozin Form B, Form C and Form D have poor phase stability and are difficult to be reproduced; canagliflozin hemihydrate Form hH1 has poor phase stability, as it did not maintain its original crystalline form in the competitive stability test in water and changed its form; canagliflozin hemihydrate Form hH2 has poor phase stability and is difficult to be reproduced. The above properties may lead to problems in their pharmaceutical formulations, including variations in active substance content, poor reproducibility, impurities increasing during storage, efficacy decreasing, and so on. Moreover, the known canagliflozin is amorphous. It is well known to those skilled in the art that amorphous forms are less stable, more hygroscopic and unsuitable for applications in solid formulations.
In order to meet the strict requirements for active substances in pharmaceutical formulations and provide more polymorph form options in formulation development, there still is a need to develop novel crystalline forms of canagliflozin.